Autoantibodies are the unifying and virtually constant concomitant laboratory feature of systemic lupus erythematosus (SLE). Project #1 of the Oklahoma SLE SCOR relies upon the experimental infrastructure provided by a group of 478 sera from 130 SLE patients. These sera were prospectively collected before diagnosis of SLE and most were collected before the onset of any clinical complaints referable to SLE. Progress with these 478 sera show that autoantibodies are present in the sera of SLE patients for many years before diagnosis. Other data from our group have characterized the humoral epitope fine specificity of Sm, nRNP, 60 kD Ro, La, and ribosomal P in SLE patients with the established clinical disease of SLE. In Project #1 we propose to use the sera collected before diagnosis to test some of the potential lessons learned from established SLE patients, as well as describing many of the earliest humoral autoimmune events which occur years before diagnosis. We propose to use the sera collected before diagnosis to evaluate the fine specificity of Sin, nRNP, 60 kD Ro, La, ribosomal P, and perhaps, other autoantigens to evaluate three hypotheses. Hypothesis #1. The fine specificity of each SLE autoantigen-autoantibody system will have only a few, or even only one, initial epitopes and a limited number of pathways for increasing the complexity of the autoantibody response. The major part of the work in Project #1 will be done with the fine specificity of individual autoantigens doing the experiments to develop individual examples that have the potential to demonstrate that this hypothesis is true. Hypothesis #2.Characteristics of autoantibody fine specificity, heavy chain class and subclass, and light chain type, variable chain composition, and antibody quantity contribute to initiation of disease and to the onset of clinical illness. In these experiments we hope to find the associations of autoantibody structure and specificity with the onset of autoimmunity and the onset of clinical illness. Hypothesis #3. The lessons established using the sera from the 130 SLE Active Duty Military subjects already collected and from the specificities spontaneously developed by other rheumatic disease patients under observation will be confirmed and extended by those recruited during the proposed funding period. We are in a position to double the size of the SLE patient serum collection with the requested funding, thereby providing improved statistical power and making our conclusions much more reliable. These experiments will help elucidate the origins of autoantibodies in SLE.